The University of Nevada, Reno and the Instituto Nacional de Enfermedades Virales Humanas (INEVH) have initiated a collaborative effort to investigate the pathogenesis, ecology and epidemiology of South American Hantaviruses. In our earlier studies we reported the presence of seven novel and phylogenetically distinct hantavirus linages in Argentina. These linages differ at the nucleotide level from 11-21 percent among themselves and 23-26 percent from North American hantaviruses. Three of the linages have been associated with hantavirus pulmonary syndrome and the other with a hemorrhagic fever with renal syndrome. One of the linages (Andes virus) is known to be transmitted directly from humans to humans and a second virus (Oran) is widespread in rodent populations in northern Argentina and is present in 25-40 percent of the native population, as compared to a greater than 1 percent exposure rate throughout Argentina. We propose to determine if the variation in clinical syndromes observed is caused by genetic differences in virus strains or genetic differences in the host. This hypothesis will be tested with the following specific aims: 1) Hantavirus strains associated with a spectrum of clinical syndromes will be examined to identify genetic differences using archived tissue samples, from patients with clinical manifestations varying from a hemorrhagic fever with renal syndrome to a disease resembling hantavirus pulmonary syndrome. 2) A comparison of the pathology of the disease in rodents infected with different hantavirus lineages will be done to determine if the epidemiologic and clinical differences associated with South American hantaviruses is caused by an altered pathogenesis of the viruses in rodents. 3. Identification of neutralizing epitopes in hantavirus glycoproteins: Human monoclonal antibody libraries will be used for the identification and mapping of neutralizing epitopes in both tissue culture and in the rodent reservoir. 4. The pattern of association and co-evolution of South American hantaviruses with their sigmodontine rodent hosts will be identified. 5. Differences in the susceptibility of different human haplotypes to infection with hantaviruses will be determined using archived tissue samples from INEVH. It is anticipated that a clearer understanding of the pathogenesis, ecology and epidemiology of South American hantaviruses will help in the prevention of outbreaks of disease caused by new world hantaviruses.